Structure-based screening of FDA-approved drugs and molecular dynamics simulation to identify potential leukocyte...

Leukocyte antigen related protein (LAR), a member of the PTP family, has become a potential target for exploring therapeutic interventions for various complex diseases, including neurodegenerative diseases. The reuse of FDA-approved drugs offers a promising approach for rapidly identifying potential LAR inhibitors. In this study, we conducted a structure-based virtual screening of FDA-approved drugs from ZINC database and selected candidate compounds based on their binding affinity and interactions with LAR. Our research revealed that the candidate compound ZINC6716957 exhibited excellent binding affinity to the binding pocket of LAR, formed interactions with key residues at the active site, and demonstrated low toxicity. To further understand the binding dynamics and interaction mechanisms, the 100-ns molecular dynamics simulations were performed. Post-dynamics analyses (RMSD, RMSF, SASA, hydrogen bond, binding free energy and free energy landscape) indicated that the compound ZINC6716957 stabilized the structure of LAR and the residues (Tyr1355, Arg1431, Lys1433, Arg1528, Tyr1563 and Thr1567) played a vital role in stabilizing the conformational changes of protein. In conclusion, the identified compound ZINC6716957 possessed robust inhibitory activity on LAR and merited extensive research, potentially unleashing its significant therapeutic potential in the treatment of complex diseases, particularly neurodegenerative disorders.